Paraneoplastic Neurlogical Disorders

Title

Definitions

•

• Many of the conditions are not exclusively paraneoplastic and can occur as primary autoimmune disorders (e.g. Myasthenia gravis)

Epidemiology

• Occur in 0.5-1% of cancer patients

• In 60% of patients neurology precedes cancer diagnosis

• Incidence higher in certain cancers

o SCLC 2-3%

o Thymoma 30-50%

Specific syndromes

Syndromes of the brain, brainstem, and cerebellum

• Focal encephalitis
• Cortical encephalitis
• Limbic encephalitis
• Brainstem encephalitis
• Cerebellar dysfunction
• Autonomic dysfunction
• Paraneoplastic cerebellar degeneration
• Opsoclonus-myoclonus

Syndromes of the spinal cord

• Subacute necrotizing myelopathy
• Motor neuron dysfunction
• Myelitis
• Stiff-person syndrome

Syndromes of dorsal root ganglia

• Sensory neuronopathy
• Multiple levels of involvement
• Encephalomyelitis,a sensory neuronopathy, autonomic dysfunction 

Syndromes of peripheral nerve

• Chronic and subacute sensorimotor peripheral neuropathy
• Vasculitis of nerve and muscle
• Neuropathy associated with malignant monoclonal gammopathies
• Peripheral nerve hyperexcitability
• Autonomic neuropathy

Syndromes of the neuromuscular junction

• Lambert-Eaton myasthenic syndrome
• Myasthenia gravis

Syndromes of the muscle

• Polymyositis/dermatomyositis
• Acute necrotizing myopathy

Syndromes affecting the visual system

• Cancer-associated retinopathy (CAR)
• Melanoma-associated retinopathy (MAR)
• Uveitis (usually in association with encephalomyelitis)

Pathogenesis

• Frequently antibody associated
• Antibodies demonstrated to have direct pathogenic role in:
• VGCC in LEMS
• ACHr in MG
• VGKC in neuromyotonia
• Antibodies to ganglionic AChR in autonomic neurpathy

Antibody	Syndrome	Associated Cancers
Anti-Hu (ANNA-1)	PEM (including cortical, limbic, brainstem encephalitis, cerebellar dysfunction, myelitis), PSN, autonomic dysfunction	SCLC, other neuroendocrine tumors
Anti-Yo (PCA-1)	PCD	Ovary and other gynecologic cancers, breast
Anti-Ri (ANNA-2)	PCD, brainstem encephalitis, opsoclonus-myoclonus	Breast, gynecological, SCLC
Anti-Tr	PCD	Hodgkin's lymphoma
Anti-Zic	PCD, encephalomyelitis	SCLC and other neuroendocrine tumors
Anti-CV2/CRMP5	PEM, PCD, chorea, peripheral neuropathy, uveitis	SCLC, thymoma, other
Anti-Ma proteinsa	Limbic, hypothalamic, brainstem encephalitis (infrequently PCD)	Germ-cell tumors of testis, lung cancer, other solid tumors
Anti-NR1/NR2 subunits of NMDA receptor	Encephalitis with prominent psychiatric symptoms, seizures, hypoventilation	Ovarian teratoma
Anti-amphiphysin	Stiff-person syndrome, PEM	Breast, SCLC
Anti-VGCCb	LEMS, PCD	SCLC, lymphoma
Anti-AChRb	MG	Thymoma
Anti-VGKCb	Peripheral nerve hyperexcitability (neuromyotonia), limbic encephalitis	Thymoma, SCLC, others
Anti-recoverin	Cancer-associated retinopathy (CAR)	SCLC and other
Anti-bipolar cells of the retina	Melanoma-associated retinopathy (MAR)	Melanoma

PEM = Paraneoplastic encephalomyelitis, PCD= paraneoplastic cerebellar degeneration, PSN = paraneoplastic sensory neuronopathy, LEMS = Lambert-Eaton, MG = Myasthenia gravis, VGCC voltage gated calcium channel, VGKC = Voltage gated potassium channel

Clinical manifestations

Diagnosis

• Antibodies detected in 60-70% of conditions

• In some conditions antibodies are found only in the CSF

• MRI

• EEG

• In patients with paraneoplastic syndrome and negative CT screen the chance of finding cancer with PET is:

o 50% if patient has classical paraneoplastic antibody

o 20% if patient has no antibodies

• Radiation exposure from screening:

o CT CAP 17mSv

o PET 25mSv

Specific Syndromes

	Antibodies
	Paraneoplastic
Syndrome	Frequent	Infrequent	Nonparaneoplastic
Limbic encephalitis	Ma2, Hu, CV2/CRMP5, anti-NR1/NR2 of NMDA receptor	Tr, VGKC	VGKC
Cerebellar degeneration	Yo, Tr, P/Q VGCC, Hu, Zic, Ri, CV2/CRMP5, Ma1-2	mGluR1; MAZ	Gliadin, GAD
Hypothalamic, brainstem encephalitis	Ma2, Hu	CV2/CRMP5
Encephalomyelitis	Hu, Zic	CV2/CRMP5, Ri, amphiphysin
Chorea	CV2/CRMP5
Opsoclonus-myoclonus	Ri	Hu, Ma2, Yo,
Stiff-person syndrome	Amphiphysin	Gephyrin, Ri	GAD
PNH (neuromyotonia)	VGKC		VGKC
Myasthenia gravis	AChR		AChR, MuSK
LEMS	P/Q-type VGCC	MysB	P/Q-type VGCC
Sensory neuronopathy	Hu
Axonal sensorimotor neuropathy	Hu, CV2/CRMP5		Monoclonal gammopathy (M protein)^b
Autonomic neuropathy	Hu	CV2/CRMP5, ganglionic AChR	Ganglionic AChR
Predominant sensory demyelinating neuropathy		MAG, ganglioside antibodies: often present with Waldenström's macroglobulinemia	MAG, ganglioside antibodies, often present with MGUS
Paraneoplastic retinopathy	Recoverin (CAR), anti-bipolar cell antibodies (MAR), anti-enolase	Tubby-like protein 1, PNR	Anti-enolase

Encephalomyelitis

• Inflammatory process with multifocal involvement of the nervous system
• Different area’s or combination of area’s affected in different patients
• Syndromes
• Cortical encephalitis
• Limbic encephalitis
• Brainstem encephalitis
• Cerebellar
• Myelitis
• Autonomic

• Frequently associated with SCLC

Limbic Encephalitis

• Acute/subacute mood and behavioural changes
• Short term memory problems
• Complex partial seizures
• Cognitive dysfunction
• Hypothalamic involvement may occur – hyperthermia, somnolence, endocrine abnormalities.
• 2/3 have multifocal involvement of the nervous system
• MRI shows T2 hyperintensity in the medial temporal lobes.
• EEG shows focal or generalized slowing or epileptiform activity in the temporal lobes
• CSF
• Moderate lymphocytic pleocytosis
• Oligoclonal bands
• Increased protein
• Normal glucose
• Associated with
• SCLC
• Testicular germ cell tumours
• Ovarian teratoma (NMDA subtype)

Treatment

• Symptoms may stabilise or decrease if tumour responds to treatment
• If good functional status consider trial of immune therapy:
• 1g IVMP for 3 days then once/week for 12 weeks (Mayo protocol, Pittock)
• IVIG and/or plasmapheresis may be useful in some cases
• Rituximab ?unlikley to be helpful as antibodies are not pathogenic

In patients with paraneoplastic syndrome and negative CT screen the chance of finding cancer with PET is:

50% if patient has classical paraneoplastic antibody

20% if patient has no antibodies

Radiation exposure from screening:

CT CAP 17mSv

PET 25mSv

o List test

o Apple

• Banana

o H

- Orangegg

• Gf

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